1. Field of the Invention
This invention relates to compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Even more specifically, the invention relates to compounds that inhibit, regulate and/or modulate kinases, particularly Tie-2. Kinase receptor signal transduction pathways related to the changes in cellular activities as mentioned above are modulated using compounds of the invention. Methods of using the compounds to treat kinase-dependent diseases and conditions are also an aspect of the invention.
2. Summary of Related Art
Improvements in the specificity of agents used to treat cancer is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms.
Protein kinases are enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell differentiation and proliferation; i.e., virtually all aspects of cell life in one-way or another depend on protein kinase activity. Furthermore, abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
Protein kinases can be categorized as receptor type or non-receptor type. Receptor-type tyrosine kinases have an extracellular, a transmembrane, and an intracellular portion, while non-receptor type tyrosine kinases are wholly intracellular.
Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily, designated the HER subfamily, is comprised of EGFR (HER1), HER2, HER3, and HER4. Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, and IR-R. The PDGP subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II. Then there is the FLK family, which is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1). The PDGF and FLX families are usually considered together due to the similarities of the two groups. For a detailed discussion of the receptor-type tyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994, which is hereby incorporated by reference.
The non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of the non-receptor type of tyrosine kinases, see Bolen, Oncogene, 8:2025-2031 (1993), which is hereby incorporated by reference.
Since protein kinases and their ligands play critical roles in various cellular activities, deregulation of protein kinase enzymatic activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer. In addition to oncological indications, altered kinase signaling is implicated in numerous other pathological diseases. These include, but are not limited to: immunological disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases. Therefore, both receptor and non-receptor protein kinases are attractive targets for small molecule drug discovery.
One particularly attractive goal for therapeutic use of kinase modulation relates to oncological indications. For example, modulation of protein kinase activity for the treatment of cancer has been demonstrated successfully with the FDA approval of Gleevec® (imatinib mesylate, produced by Novartis Pharmaceutical Corporation of East Hanover, N.J.) for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers. Gleevec is a selective Abl kinase inhibitor.
Modulation (particularly inhibition) of cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. Drug Disc Technol 2001 6, 1005-1024), is an attractive goal for development of small-molecule drugs. Anti-angiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularization, including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. As well, cell antiproliferative agents are desirable to slow or stop the growth of tumors.
One particularly attractive target for small-molecule modulation, with respect to antiangiogenic and antiproliferative activity is Tie-2. Tie-2 (also called TEK) is a member of the receptor tyrosine kinase (RTK) family, which is expressed primarily in endothelial cells and early hemopoietic cells, and plays a critical role in the processes of vasculogenesis and angiogenesis. As such, Tie-2 has been shown to participate in endothelial cell migration, sprouting, survival and periendothelial cell recruitment during angiogenesis.
The angiopoietin family of growth factors regulates Tie-2 activity through a combination of agonistic and antagonistic extracellular ligands. Binding of the ligands, Angiopoietin-1 (Ang-1) or Ang-4 by Tie-2 induces autophosphorylation resulting in an increase of receptor dependent signaling, while binding to Ang-2 and Ang-3 results in down regulation of receptor activity. Ang-1 signaling through Tie-2 facilitates later stages of vascular development by modulating cell-cell, and cell-matrix interactions, resulting in the survival and stabilization of newly formed blood vessels.
Tumor growth progression requires the recruitment of new blood vessels into the tumor from preexisting vessels. Accordingly, Tie-2 expression has been demonstrated on a wide variety of tumor types including ovarian, breast, renal, prostate, lung, thyroid, myeloid leukemia, hemangiomas, melanomas, astrocytomas, and glioblastomas. Tie-2 activation has also been linked to venous malformations (VM), the most common form of vascular morphogenesis in humans. As well, an activating mutation in the kinase domain of Tie-2 occurs in multiple families who exhibit a dominantly inherited form of VM. Tie-2 has been linked to multiple cancer types, including ovarian, breast, renal, prostate, lung, thyroid, myeloid leukemia, hemangionias, melanomas, astrocytomas, and glioblastomas (See: Shirkawa et al Int J Cancer 2002 Jun. 20; 99(6):821-8; Tanka et al Clin Cancer Res 2002 May; 8(5):1125-31; Mitsutake et al Thyroid 2002 February; 12(2):95-9; Muller et al Leuk Res 2002 February; 26(2):163-8; Yu et al Am J Pathol 2001 December; 159(6):2271-80; Pomyje et al Melanoma Res 2001 December; 11(6):639-43; Harris et al Clin Cancer Res 2001 July; 7(7):1992-7; Wrumback et al Anticancer Res 2000 November-December; 20(6D):5217-20; Ding et al Deuro-oncol 2001 January; 3(1):1-10; Takahama et al Clin Cancer Res 1999 September; 5(9):2506-10; Stratmann et al Am J Pathol 1998 November; 153(5):1549-66; and, Kukk et al Br J Haematol 1997 July; 98(1):195-203). Additionally, activation of Tie-2 has been linked to the vascular dysmorphogenesis syndrome, venous malformation (See: Vikkula et al Cell 1996 December; 87(1):1181-1190). Thus modulation of Tie-2 is desirable as a means to treat cancer and cancer-related disease.
Accordingly, the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of kinases, particularly Tie-2, is desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis, and is an object of this invention.